In the 1930s and 1940s, some scientific and clinical evidence suggested that there might be beneficial uses of vitamins C, E and B-3 in large doses. Experiments in the 1930s with larger doses of vitamin C were superseded by Fred R. Klenner's development of megadose intravenous vitamin C treatments in the 1940s. William Kaufman, MD, PhD, published two books in the 1940s that detailed his treatment of arthritis with frequent, high doses of niacinamide.

In 1954, Professor R. Altschul and Abram Hoffer, MD, PhD, applied large doses of the immediate release form of niacin (Vitamin B-3) to treat hypercholesterolemia (high cholesterol). High doses of niacin were shown to be more effective than conventional treatments in the Canner study of the Coronary Drug Project, a large-scale, prospective, randomized, controlled trial to reduce long term total mortality, showed 11% reduction in mortality at 15 years follow up with only 6 years of niacin treatment. The other conventional approaches (two estrogen regimens, dextrothyroxine and clofibrate) -- treatments that are no longer standard of care -- were ineffective. Niacin is used to treat hypercholesterolemia because of its low cost and its unique ability to broadly improve lipid profiles.

The 1956 publication of Roger J. Williams' Biochemical Individuality introduced concepts for individualized megavitamins and nutrients. In the 1960s, biochemist Irwin Stone, author of The Healing Factor, observed that vitamin C's utility in the megadose treatments of human disease parallels the amounts of vitamin C physiologically produced in most animals and postulated humans' evolutionary loss of this capability. Megavitamin therapies were also publicly advocated by Linus Pauling in the late 1960s.

Several orthomolecular megavitamin protocols have been publicized. While formal medical recognition of niacin therapy for hypercholesterolemia followed confirmation by William Parsons of the Mayo Clinic (1956) and the Canner study (1986), the success of several popular books since the 1980s has made the public more aware of niacin's effective megavitamin therapy for dyslipidemias (abnormal lipid levels in the blood). Pauling's advocacy of megadoses of vitamin C for colds, beginning in the 1960s, and later for cancer, made millions aware of the concept of megavitamin treatment in disease. Pauling's vitamin C recommendations are lower than some modern recommendations.